Bounty of Novel Drugs Ushers In New Era for ALK-Positive NSCLC

Jane de Lartigue, PhD

Published: Tuesday, Feb 13, 2018

During the past decade, ALK inhibitors have followed a rapid trajectory from bench to bedside, taking over from chemotherapy as standard frontline treatment for patients with advanced non– small-cell lung cancer (NSCLC) with ALK gene rearrangements.

The first-to-market advantage went to crizotinib (Xalkori), which was initially approved in 2011. That drug has been joined by 3 more potent ALK inhibitors for use in the secondline setting for patients with locally advanced or metastatic disease: alectinib (Alecensa), ceritinib (Zykadia), and brigatinib (Alunbrig). Now, a new era is shaping up in the treatment of ALK-positive NSCLC. Indications for alectinib and crizotinib have recently been expanded into frontline settings and findings from the ALEX trial have demonstrated alectinib’s superiority over crizotinib.

The main limitation concerning the impact of these drugs is the development of resistance, which typically arises quickly and often involves progression to the central nervous system (CNS). Newer ALK inhibitors continue to be developed to counter resistance mechanisms.

Particularly noteworthy, lorlatinib targets the broadest range of resistance mechanisms to date and, if approved, might add to a therapeutic arsenal that could be deployed sequentially over time as the tumor evolves, with the potential to transform ALK-positive NSCLC into a chronic disease.

Adopting Orphan ALK

As its name suggests, the anaplastic lymphoma kinase is a receptor tyrosine kinase that was first identified through its aberrant expression in anaplastic large cell lymphoma.1

ALK spans the cell membrane, with its tyrosine kinase region located on the inside of the cell and, following ligand binding, it activates a complex network of different proteins involved in a variety of signaling networks, including the Janus kinase/ signal transducer and activator of transcription, phosphatidylinositol-3-kinase/ AKT, and mitogen-activated protein kinase pathways (FIGURE2).

Figure. ALK Signaling Pathways in Lung Cancer2

Beyond this, little is known about the precise biological function of the ALK protein and, until recently, it was considered an “orphan” receptor, with no known activating ligand. Studies have established the augmentor α and β proteins (also known as FAM150B and A, respectively) as the ligands for ALK. Other research suggested that heparin may act as an ALK ligand, but this has not been confirmed in subsequent work, although it may bind to FAM150A and regulate ALK activation in that manner.3

A Lung Cancer Driver

In 2007, a chromosomal rearrangement involving the ALK gene, which resulted in the expression of a dysfunctional fusion protein, was identified in a resected tumor specimen from a 62-year old patient with lung cancer.4

Although ALK fusions are found in other types of lung cancer,5 they are most prevalent and best characterized in NSCLC. Multiple types of ALK fusions now have been identified in patients with NSCLC, but the most common is the EML4-ALK fusion. A small inversion in chromosome 2 results in the fusion of the front end of the echinoderm microtubule-associated protein-like 4 (EML4) gene to the back end of the ALK gene.

More than a dozen variants of the EML4-ALK fusion have been identified in NSCLC to date, but all retain the ALK kinase domain, juxtaposed to EML4’s promoter, which results in unfettered activation of ALK. This drives many of the hallmarks of cancer cells through hyperactivation of downstream pathways that play fundamental roles in cell growth, proliferation, and survival, among other cellular processes.

ALK fusions are estimated to occur in between 3% and 7% of cases of NSCLC and define a distinct clinical and histological subset of the malignancy; patients are typically younger, never or light smokers, and have adenocarcinoma histology.6-8

Bench to Bedside

National Comprehensive Cancer Network (NCCN) and International Association for the Study of Lung Cancer guidelines recommend testing all patients who present with advanced NSCLC for ALK fusions because clinical trials have demonstrated the sensitivity of ALK-positive cancers to ALK inhibition.9,10

The development of ALK inhibitors has become a shining example of the power of personalized medicine, with a growing number of these agents proceeding from bench to bedside in the span of less than a decade and replacing chemotherapy as the preferred frontline option in the treatment of patients with ALK-positive NSCLC.